The PI has isolated HIV-1 viruses from infected humans that, despite relatively high viral loads, do not exhibit evidence of clinical progression. Some of these viruses appear to replicate well in a CD4 lymphocyte single cell killing (CD4-SCK) assay designed by the applicant, but exhibit lower levels of induced cytopathic effects. Other viruses isolated from these individuals replicate comparably but induce greater cytopathic effects in CD4-SCK assay. The PI proposes: (1) To generate molecular proviral clones of these HIV-1 isolates that duplicate the observed phenotypes with respect to cell killing; (2) To use recombinant viruses constructed between cytopathic and noncytopathic variants to identify the molecular determinants of cytopathic effect in the CD4-SCK assay and in a NOD/LtSz-scid mouse model. (3) To determine the potential significance of the identified cytopathic determinant in the course of pathogenesis in the non-progressor patients.